Matt Hoffman

This is part 2 of a special 3-part multimedia series. For part 1, 

In the early days of migraine care, the major concern for physicians lay in the general lack of treatment options. This was driven, in part, by a less-than-spectacular amount of literature pointing to the biologic mechanisms and pathways at play in the disease, to the point that outside of few circles of migraine specialists, the belief in a neurologic basis of the disease was waning.

Now, some 30 years and a number of new approvals later, the field has been met with an inflection point. The challenge is no longer in the ability to treat patients (though access to certain medications remains an issue) but in the identification of them and the subsequent maximization of their care. Where physicians were once left with no choice but to dismiss patients for lack of options, now they stand able to help, but uncertain of what will provide the most benefit. Additionally, a better understanding of the biology of migraine and the utility of these medications has opened the window for increased identification and education of patients, as well as an improved familiarity with their needs.

For migraine specialists, it is certain that although the past was dark, the future is quite bright. But as physicians such as Richard B. Lipton, MD, know all too well, the patients of the present do not necessarily benefit from the advances of the future. In the meantime, the focus has shifted from simply developing options to demonstrating optimization—both for the future and for the now. This, in turn, has resulted in a blurring of the lines, so to say, between preventive and acute care.

“For many years, we drew a bright line distinguishing between acute treatment and preventive treatment, and we really thought of them as separate entirely,” Lipton

, who is the Edwin S. Lowe Professor and vice-chair of neurology, a professor of epidemiology and population health, and a professor of psychiatry and behavioral sciences at the 

. “When you're studying preventive treatment, you study the reduction in monthly headache days, and when you study acute treatments, you study relief of an ongoing attack 2 hours after taking drugs, in general. We viewed the differences between acute and preventive treatment as fundamental and biologically based.”

Lipton elucidated that specifically, 2 events caused this reconsideration of the bright line that was previously painted between acute and preventive treatments—the CGRP agents and the neuromodulation devices, which have shown to have both preventive and acute applications. This knowledge of the disease has improved, and now the understanding of the patients with it and their needs must improve as well. As such, over the last decade of this modern age of care, the gathering of epidemiologic data has certainly come to the forefront.

The Metamorphosis of Migraine: Discovery and Development

For example, the development of drugs targeting calcitonin gene-related peptide (CGRP) has led to effective and targeted treatments for the prevention of migraine for essentially the first time in history. A welcomed step forward, of course, but as studies have shown, not every patient derives benefit from these drugs. On top of this, patient prevalence is quite high. A 2018 systematic review suggested that 1 in 6 Americans suffers from the debilitating condition,1 and the Migraine Research Foundation estimated it as the third most prevalent disease in the world.2 In 2019, another study noted that the 1-year prevalence of incident migraine was 2.2% (1.5% in men and 3.1% in women), with close to 12% of patients found to have severe disability related to the condition.3 These findings add weight to the need to answer the burning questions of which patients need preventive or acute care options, or both.

“The reality is, not everyone with migraine needs a preventive at all. Our estimate is that a little under 40% of people with migraine are candidates for preventive therapy. For the vast majority, all they need is acute treatment,” Lipton said.

“There are people who appropriately self-treat with over-the-counter medications [OTCs] and have no unmet needs. But there are also people who are using OTCs only who've never seen a doctor,” he explained. “They are barriers at the level of seeking care, there are barriers at the level of diagnosis, and then if you seek care and get a diagnosis, are you getting minimally effective treatment?”

As well, each additional approval has come with its own challenges in incorporation into care. Lipton explained that the triptans, as well as opioids and barbiturate combination agents, can actually worsen severity and cause patients to develop medication overuse headache (MOH) if not taken carefully, adding to patient education as a priority. Epidemiologic data suggest that the prevalence of MOH is highest among adults aged 30 to 50 years, with a preponderance of cases in female patients versus male patients (the ratio ranging from 3:1 to 4:1). Furthermore, between 21% and 52% of pediatric patients with chronic headache meet the diagnostic criteria for MOH.

Also, as access to new agents increases, so does the patient awareness about the disease; more treatment options means more patients willing to try treatment. But as the number of patients increases, the ability of migraine specialists to see every individual decreases similarly.

Studies have also revealed challenges in patient education about the disease, in spite of increasing awareness. Many patients, it seems, are still seeking care either unsuccessfully, or in the wrong places. In the MAST study, only approximately 21% of persons with migraine had reported a diagnosis by a health care provider, despite the lifetime rate of medical consultation for headache being 79.8%.3 Additionally, the OVERCOME study revealed that migraine is most often seen by primary care providers, with just about 15% of individuals with migraine visiting headache specialists, and another 15% seeking care from pain specialists.5

This leads to concerns not only about patients possibly getting inappropriate treatments but about the education around migraine care for physicians who do not specialize in headache disorders. Particularly, there is a glaring need in primary care. Additional data from OVERCOME revealed that these physicians prescribe triptans to 33% of patients with migraine and opioids, which many headache specialists do not recommend, to 27%.6

“I think a huge gap is, first of all, giving primary care doctors the time that they need to manage migraine, and getting them up to speed on emerging therapies,” Lipton said. “The majority of [non-specialist-treated] patients are seen by pediatricians, internists, family doctors, and gynecologists. It's a little outrageous for me to say that primary care doctors should do a better job in migraine management, but I do think headache is part of the remit of primary care doctors. I'm very interested in improving migraine care in primary care settings, and I think there's a huge opportunity there.”

Lipton also noted that patients tend to fall off from treatment quite rapidly due to lack of efficacy or lack of diagnosis, as well, even if they are among those who have sought care for their migraines. He estimated that of those with migraine and disability on their current treatment, perhaps 60% are currently seeking care, and of those, perhaps 70% have gotten an actual diagnosis of migraine from a healthcare professional.

“At the end of the day, there are a lot of people with migraine and disability who are not reversing all 3 of those barriers to effective treatment,” Lipton explained. 

Although migraine care has definitively taken great leaps forward in the pharmacologic sense, there is certainly more to glean about the use of these drugs, and a number of pressing issues remain unaddressed. Increasing patient awareness and improving their personal disease management is still a priority and cultivating the non-headache physician's understanding of migraine is paramount.

Though for Lipton, even in light of these challenges, the coming years are ripe with opportunity. “We never know what we're going to learn in the future,” he said.

REFERENCES
1. Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. 

. 2018;58(4):496-505. doi: 10.1111/head.13281.
2. Migraine Research Foundation. About Migraine. MRF website. Updated 2020. Accessed September 15, 2020. migraineresearchfoundation.org/about-migraine/migraine-facts.
3. Lipton RB, Reed ML, Munjal S, et al. One-year incidence of migraine in the US population: results from the Migraine in America Symptoms and Treatment (MAST) study. 

. 2019;59:9. doi: 10.1111/head.13407
4. Vandenbussche N, Laterza D, Lisicki M, et al. Medication-overuse headache: a widely recognized entity amidst ongoing debate. 

. 2018;19(1):50. doi: 10.1186/s10194-018-0875-x.
5. Lipton RB. Patterns of diagnosis, consultation, and treatment of migraine in the US: results of the OVERCOME study. Presented at: 

 61st Annual Scientific Meeting; July 11-14, 2019; Philadelphia, PA.
6. Buse DC, Nicholson RA, Araujo AB, et al. Migraine care across the healthcare landscape in the United States among those with 4 or greater migraine headache days per month: results of the OVERCOME study. 

Articles

The ongoing fight to add to the epidemiologic understanding of migraine is explored in part 2 of this special 3-part multimedia series on the evolution of migraine care.

The Metamorphosis of Migraine: Evidence and Epidemiology

, September 12–16, 2020, a top abstract presentation was given that revealed insight into the impact of loneliness and social isolation on patients with Parkinson disease. In particular, it covered how these statuses of well-being can extraordinarily detrimental for patients.

Presented by lead author Indu Subramanian, MD, director, VA Southwest Parkinson’s Disease Research, Education, and Clinical Centers, 

the data were analyzed from a survey study of more than 1700 patients with idiopathic Parkinson from the CAM Care PD study. All told, those data showed that those who reported feeling lonely had higher PRO-PD scores—even higher than those for smoking and high stress.

To find out more about how recognizing loneliness as a risk factor for worsened disease severity can lead to more proactive prevention of social isolation, 

 spoke with Subramanian. She offered some background on what inspired the study and provided her perspective on the need to address loneliness in patients.

: Could you provide some insight into what prompted this specific work?

 I've been a Parkinson's doctor for about 20 years, and I've been really interested in looking at what makes patients have a better quality of life and reduce their symptoms. I have been Western-trained as a movement disorder neurologist, but also have this background in integrative medicine and have been interested in using yoga and mindfulness as applications to possibly help our patients. Going to those conferences about integrative medicine, I learned about these social determinants of health that were really unknown to me from medical school, and I was really fascinated by the concept of loneliness and social isolation.

We ended up having this web survey that we administer to patients. There are about 2000 patients involved in our study, and about 1800 of them or so are patients with Parkinson's. We have a whole host of questions that we asked them about things that they can modify that might have something to do with how their quality of life is currently. Things like exercise and diet. We started looking at some of these other determinants as well, such as loneliness and social isolation, by asking specific questions like, “Are you lonely?” and “Do you have a lot of friends?” things like that. When we looked at the data, I initially was really excited about yoga and its effects. But we ended up looking at the loneliness indicators, and saw that loneliness is actually a hugely bad prognostic indicator for these patients. It's as bad for you to be lonely with Parkinson's as the beneficial effects of exercising 7 days a week for 30 minutes a day is good for you. So, it's a really huge determinant of wellness in this population, and I think it's all the more important to care about this due to COVID-19.

Our research was conducted before the pandemic, and we have a survey that goes out every 6 months, so we'll see how this cohort is doing moving forward—we've added some additional questions around loneliness and ways to measure it. But I think it'll be really important for us as a medical community to care about our patients no matter what the disease state is. There's actually data looking at aging populations and the data suggests that it's as bad for you to be lonely as it is if you smoked a half a pack of cigarettes every day or if you are obese. This is a huge determinant of help just in general populations, and in Parkinson's patients specifically, I think it's really a sort of big red flag if somebody is lonely and isolated.

Do you think having this perspective on patient’s lives fits into the comprehensive care model?

I think that's probably why somebody like me got interested in some of these other things. I ended up doing a yoga teacher training and did a lot of mindfulness training actually at the VA where I run a Center of Excellence. I've just been drinking it all in, I think it's really important to think about disease and health in a very different way. Even the World Health Organization talks about diseases not just as the absence of wellness, but actually this holistic model of true mental, spiritual, and physical well-being.

The VA has actually been quite cutting edge in that regard. They have this program called the Whole Health Program where the patient's kind of in the middle, and then all the things that make a difference for a patient's health are around them. Things like what they would eat, the people who are in their lives—all these different factors. In a sort of sense that you're not just taking care of Mr. Smith with a tremor today, but really thinking about Mr. Smith and where he lives and all the people that impact him. Can he actually get green vegetables if I prescribe that to him? Can Mr. Smith sign into the online yoga program? I think we have to think about these patients in a very different way.

The COVID-19 pandemic has really made us think outside the box. We're used to seeing a patient in our office with our white coat and the patient sitting in that chair and us typing. Now, I'm seeing them at home, seeing what's in the background. I've really been so interested in the sort of stuff that's in my patients' homes, or what's down the street for them to access, and all the things that make them healthy and well. It's really made me pause and think about what really matters, and I think it's an important time for a lot of these things to be highlighted. People are becoming more open-minded to the concept of health as this sort of holistic kind of approach and thinking about the determinants of health in a very different way. We see that race and ethnicity matter so much to who's dying from COVID-19. We see that something that impacts somebody across the world can impact me like a virus can spread or we can impact each other. It's just such a differently connected way of thinking about health these days that is quite profound as a pivot of change. I'm excited to see what the future holds, but I think we have an opportunity to really think outside that box and intervene in ways that we may never have done before.

What does this suggest about physicians inquiring with their patients about loneliness?

One of the things that I've been really interested in is the fact that I've never actually asked about that. You know, if somebody comes into my office with a wife and they seem to be getting along, I just assume that man is not lonely. But from my reading and learning about this, there were a lot of interesting things that were revealed to me. Actually, in order to be not lonely, it's important for you to have quality relationships in 3 spheres.

One is the intimate sort of sphere, maybe being connected to a partner or a spouse. The second is the sort of relational loneliness of having people that are in your circle of friends that care about you, and that you can confide in. The third is that you're connected to a collective group in society that has a purpose that you share. For my veterans, that might be being a veteran. For my Parkinson's patients, it might be joining a support group. These things each actually have to be quite fulfilling for people to not feel lonely, and so I think we have to ask patients in a different way. We have to say, “How are you doing?” and “Are you lonely?” We have to ask, “Do you have people in these 3 spheres?” I think it's quite powerful to care about patients this way. It’s a very different way than we may have done in the past.

REFERENCE
Subramanian I, Mischley L, Farahnik J. Loneliness/Social Isolation as a Risk Factor for Worsened Parkinson Disease Severity. Presented at MDS Virtual Congress; September 12–16, 2020.

The director of the VA Southwest Parkinson’s Disease Research, Education, and Clinical Centers offered background the inspiration for the study and why loneliness should be addressed in these patients.

Addressing Loneliness and Social Isolation in Patients With Parkinson Disease

Interim results of a long-term study (NCT02542696) of apomorphine sublingual film (Kynmobi; Sunovion) presented at 

, September 12–16, 2020, suggest that the recently approved treatment is safe and effective as an on-demand therapy for addressing OFF episodes in patients with Parkinson disease.

Led by Stewart Factor, DO, director, Movement Disorders Program, and Vance Lanier Chair of Neurology, Emory University School of Medicine, the analysis included 345 patients who received at least 1 dose of apomorphine sublingual film (median exposure: 141 d [range, 1–723]).

By Week 48 of the study, 84% of patients (27 of 32) reported full ON status 30 minutes post-dose. Comparatively, those rates were 78% (267 of 342) at Week 1, 78% (171 of 218) at Week 12, 74% (117 of 159) at Week 24, and 89% (41 of 46) at Week 36.

"It has a significant effect on switching people from OFF to ON rather quickly, most patients within 15 minutes," Factor told 

. "This responsiveness, in this poster, has been shown to be maintained over 48 weeks. The initial double-blind study showed 12-week data, so this really demonstrated that tolerance doesn't appear to occur at least out to 48 weeks."

Additionally, at Week 24, the changes from pre-dose state in mean Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III scores were reductions of 13.3 at 15 minutes post-dose, 20.1 at 30 minutes, and 19.2 points at 60 minutes. Similar results were also observed for these time points at Week 36—reductions of 11.2, 21.6, and 20.8, respectively—and Week 48—reductions of 13.3, 22.6, and 21.1, respectively.

Parkinson Disease Gene Therapy VY-AADC01 Proves Safe With Signs of Efficacy

Notably, in the agent’s comparison against placebo in clinical trial CTH-300 (NCT02469090), the primary end point of change from pre-dose to 30 minutes post-dose at Week 12 in MDS-UPDRS Part III score was significantly improved with apomorphine sublingual film (–11.1) compared to placebo (–3.5), for a least-squares mean difference of –7.6 (

This analysis included 425 patients who received ≥1 dose during the dose-titration phase (new patients, n = 347; rollover patients from phase 2/3 studies, n = 78), though 60 patients (14%) discontinued prior to the long-term safety phase. Those discontinuations were due to AEs (n = 26; 6%), withdrawal of consent (n = 16; 4%), lack of efficacy (n = 12; 3%), protocol violation (n = 4; 1%), and other (n = 2; <1%).

As for safety, treatment-related adverse events (AEs) occurred in 85% of patients, with the majority (66%) being rated as mild. The most common, occurring in ≥10% of patients, included nausea (27%), yawning (12%), dizziness (11%), and somnolence (11%). There were oral treatment-related AEs, most notably mucosal erythema (8%) and lip swelling (5%), which were the only such to occur in 5% or more of patients. Syncope occurred in 2%.

In total, 31% of patients experienced an AE leading to discontinuation, most of which were nausea (6%), lip swelling (3%), and dizziness (2%). There were 4 deaths were reported, none deemed drug-related.

"I think most people would be concerned about oral lesions that could occur in this long-term study—only about 8% dropped out because of these events," Factor explained. "It's very possible that, in practice, if they were to hold the drug until the lesions clear, they may be able to restart it again. That's something we need to see with time and experience."

Most patients utilized doses ranging from 10–20 mg during both the dose-titration (10 mg: 18%, n = 63; 15 mg: 27%, n = 92; 20 mg: 22%, n = 77) and the long-term safety phases (10 mg: 18%, n = 63; 15 mg: 25%, n = 85; 20 mg: 23%, n = 78). Although, a dose of 25 mg was taken by 16% (n = 56) and 17% (n = 57) of those in the 2 phases, respectively. Doses of 30 mg and 35 mg were administered to 8% (n = 28) and 8% (n = 29), respectively, during titration and 10% (n = 35) and 8% (n = 27) in the long-term phase, respectively.

The treatment was approved by the FDA as the first therapy for OFF episodes associated with Parkinson disease that is administered sublingually in May 2020, based on the data from the CTH-300 trial. In January 2019, the 

FDA sent a complete response letter (CRL)

 to Sunovion in response to its original filing in mid-2018 for the sublingual film, requesting additional information and analyses but no additional clinical studies. After then resubmitting the application in November 2019, its acceptance set its Prescription Drug User Fee Act (PDUFA) action date.

Apomorphine sublingual film is meant to be used in on-demand treatment of all types of motor OFF episodes, including morning and unpredictable OFF, delayed/partial ON, and end-of-dose wearing OFF episodes. Sunovion has noted in releases that these episodes are experienced by 40% to 60% of patients, and limited treatment options are available to treat the population. This treatment joins Acorda’s inhaled levodopa (Inbrija) and US WorldMeds' apomorphine hydrochloride injection (Apokyn) as one of the few acute treatment options for OFF episodes.

REFERENCES
1. Factor S, Ondo W, Isaacson S, Bhargava P, Navia B. A Long-Term Safety, Tolerability, and Efficacy Study of Apomorphine Sublingual Film for On-Demand Treatment of “OFF” Episodes in Patients With Parkinson’s Disease: Interim Results. 

Presented at: MDS Virtual Congress; September 12–16, 2020. Abstract 888. 


2. Navia B, Factor S, Pahwa R, et al. Efficacy and Safety of Sublingual Apomorphine film (APL-130277) for the Treatment of OFF Episodes in Patients with Parkinson's Disease: Results from a Double-Blind, Placebo-Controlled Trial. Presented at: 2nd Pan American Parkinson's Disease and Movement Disorders Congress; Miami, FL, June 24-28, 2018. LBA03.
3. Sunovion Announces U.S. FDA Approval of Kynmobi (apomorphine hydrochloride) Sublingual Film for the Treatment of Parkinson’s Disease OFF Episodes. News Release. Sunovion; May 21, 2020. Accessed September 16, 2020. https://www.businesswire.com/news/home/20200521005786/en/Sunovion-Announces-U.S.-FDA-Approval-KYNMOBI%E2%84%A2-apomorphine

The recently approved apomorphine sublingual film (Kynmobi; Sunovion) maintained efficacy over the long-term, with at least 74% of patients experiencing full ON within 30 minutes post-dose at each time point.

Apomorphine Sublingual Film Shows Long-Term Efficacy in OFF Episode Treatment

The results of an evaluation of cerebrospinal fluid (CSF) tau and amyloid-beta proteins suggest that these CSF biomarkers, particularly tau, might serve as predictive markers of early disability and worsened prognosis in patients with multiple sclerosis (MS).

All told, the markers of neurodegeneration were assessed in 109 patients, 82 of whom had relapsing-remitting MS. Those with higher CSF tau levels at the time of diagnosis developed higher disability as measured by MS severity score (MSSS) and MSSS age-related score (ARMSS), independent of age. No associations were found for amyloid-beta.

The data were presented by Eleonora Virgilio, MD, doctoral student, University of Piemonte Orientale, at 

MS Virtual 2020, the 8th joint ECTRIMS-ACTRIMS meeting

, September 11–13, 2020. “To our knowledge, no other studies report a correlation of CSF Tau with both MSSS and ARMSS. Longer follow-up, larger population, and extended analysis of radiological data are needed, to confirm a predictive and prognostic role of our biomarkers both at baseline and follow up,” they wrote.

The mean follow-up for the study was 4 years (standard deviation [SD], 5), with the mean CSF values of tau being 128.5 pg/mL (±69) and of amyloid-beta being 557.7 pg/mL (±258.6). About two-thirds (62.4%) of the cohort was female, the mean age at onset of disease was 36.3 years, and the mean diagnosis age was 38.7 years. Median Expanded Disability Scale Status (EDSS) score was 1.5.

The aforementioned group with higher tau values at disease onset predicted early disability withthe MSSS (β, 0.258; R2 0.24; 95% CI, 0.02–0.14; 

= .009) and with ARMSS (β, 0.252; R2 0.22; 95% CI, 0.02–0.12; 

Levodopa-Carbidopa Intestinal Gel Superior to Immediate-Release Capsules for ON Time Without Dyskinesia

“We also found a trend of higher tau level and lower amyloid-beta levels with higher T2 white matter lesion load and spinal cord involvement, still statistically not significant,” Virgilio and colleagues wrote. Approximately half of the study cohort, 54.1%, reported high white matter lesion load, and similarly, just under half, 45.9%, reported spinal cord involvement. The proportion of patients with contrast-enhanced lesions was 25.7%.

CSF amyloid-beta and tau levels were determined with commercial enzyme-linked immunosorbent assay in newly diagnosed patients with MS. The group collected demographic, clinical, and radiological data at baseline and at the last clinical follow-up.

Neurofilament light chain (NfL) protein has dominated the conversation about MS-related biomarkers over the last few years, though a number of other projects have explored additional evidence of effective biomarkers. In early 2020, the results of one such study revealed that lowered levels of the total radical-trapping antioxidant parameter (TRAP), adiponectin, zinc, and soluble tumor necrosis factor (TNF)-α receptor (sTNFR) 2 are associated with the disease activity of MS. Notably, these antioxidants were deemed more important biomarkers than TNF-α signaling and nitro-oxidative biomarkers.

Conducted by Edna Maria Vissoci Reiche, MD, and colleagues, the study included 174 patients with MS, including 5 with clinically isolated syndrome (CIS), 144 with relapse-remitting MS (RRMS), and 25 with progressive clinical forms of MS. In total, 5 of those patients had primary progressive MS (PPMS) and 20 had secondary progressive MS (SPMS).

The data revealed that patients with MS all had lowered levels of TRAP, zinc, adiponectin, and SH groups (all 

= .001). Patients with this combination of antioxidants were correctly classified in 95.5% of cases, with a sensitivity of 95.7% and specificity of 95.1%. Investigators noted a .986 (

0.005) area under the curve (AUC)/receiver operating characteristic (ROC) curve based on these 4 antioxidants. Additionally, those with that combination of antioxidants displayed higher levels of AOPP (

REFERENCES
1. Virgilio E, Vecchio D, Crespi I, et al. Biomarkers of neurodegeneration, in particular Tau protein, may predict early disability in Multiple Sclerosis patients. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract PS03.02.
2. Mezzaroba L, Simao AC, Oliveira SR, et al. Antioxidant and anti-inflammatory diagnostic biomarkers in multiple sclerosis: a machine learning study. 

 (2020).doi : 10.1007/s12035-019-01856-7.

Data show that higher CSF tau levels at diagnosis correlated with worse disability independent of age, though no such associations were identified with amyloid-beta.

Author | Matt Hoffman

Articles

The Metamorphosis of Migraine: Evidence and Epidemiology

Addressing Loneliness and Social Isolation in Patients With Parkinson Disease

Apomorphine Sublingual Film Shows Long-Term Efficacy in OFF Episode Treatment

Tau Levels May Predict Early Disability, Worse Prognosis in MS